Alongshan Virus Infection in Rangifer tarandus Reindeer, Northeastern China.

We investigated Alongshan virus infection in reindeer in northeastern China. We found that 4.8% of the animals were viral RNA-positive, 33.3% tested positive for IgG, and 19.1% displayed neutralizing antibodies. These findings suggest reindeer could serve as sentinel animal species for the epidemiologic surveillance of Alongshan virus infection.

Bluetongue Virus Serotype 3 and Schmallenberg Virus in Culicoides Biting Midges, Western Germany, 2023.

In October 2023, bluetongue virus serotype 3 (BTV-3) emerged in Germany, where Schmallenberg virus is enzootic. We detected BTV-3 in 1 pool of Culicoides biting midges collected at the time ruminant infections were reported. Schmallenberg virus was found in many vector pools. Vector trapping and analysis could elucidate viral spread.

Identification and characterization of three monoclonal antibodies targeting the SFTSV glycoprotein and displaying a broad spectrum recognition of SFTSV-related viruses.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.

Ecology and geography of Cache Valley virus assessed using ecological niche modeling.

BACKGROUND: Cache Valley virus (CVV) is an understudied Orthobunyavirus with a high spillover transmission potential due to its wide geographical distribution and large number of associated hosts and vectors. Although CVV is known to be widely distributed throughout North America, no studies have explored its geography or employed computational methods to explore the mammal and mosquito species likely participating in the CVV sylvatic cycle. METHODS: We used a literature review and online databases to compile locality data for CVV and its potential vectors and hosts. We linked location data points with climatic data via ecological niche modeling to estimate the geographical range of CVV and hotspots of transmission risk. We used background similarity tests to identify likely CVV mosquito vectors and mammal hosts to detect ecological signals from CVV sylvatic transmission. RESULTS: CVV distribution maps revealed a widespread potential viral occurrence throughout North America. Ecological niche models identified areas with climate, vectors, and hosts suitable to maintain CVV transmission. Our background similarity tests identified Aedes vexans, Culiseta inornata, and Culex tarsalis as the most likely vectors and Odocoileus virginianus (white-tailed deer) as the most likely host sustaining sylvatic transmission. CONCLUSIONS: CVV has a continental-level, widespread transmission potential. Large areas of North America have suitable climate, vectors, and hosts for CVV emergence, establishment, and spread. We identified geographical hotspots that have no confirmed CVV reports to date and, in view of CVV misdiagnosis or underreporting, can guide future surveillance to specific localities and species.

Characterization of a natural 'dead-end' variant of Schmallenberg virus.

Schmallenberg virus (SBV) belongs to the Simbu serogroup within the family Peribunyaviridae, genus Orthobunyavirus and is transmitted by Culicoides biting midges. Infection of naïve ruminants in a critical phase of gestation may lead to severe congenital malformations. Sequence analysis from viremic animals revealed a very high genome stability. In contrast, sequence variations are frequently described for SBV from malformed fetuses. In addition to S segment mutations, especially within the M segment encoding the major immunogen Gc, point mutations or genomic deletions are also observed. Analysis of the SBV_D281/12 isolate from a malformed fetus revealed multiple point mutations in all three genome segments. It also has a large genomic deletion in the antigenic domain encoded by the M segment compared to the original SBV reference strain 'BH80/11' isolated from viremic blood in 2011. Interestingly, SBV_D281/12 showed a marked replication deficiency in vitro in Culicoides sonorensis cells (KC cells), but not in standard baby hamster kidney cells (BHK-21). We therefore generated a set of chimeric viruses of rSBV_D281/12 and wild-type rSBV_BH80/11 by reverse genetics, which were characterized in both KC and BHK-21 cells. It could be shown that the S segment of SBV_D281/12 is responsible for the replication deficit and that it acts independently from the large deletion within Gc. In addition, a single point mutation at position 111 (S to N) of the nucleoprotein was identified as the critical mutation. Our results suggest that virus variants found in malformed fetuses and carrying characteristic genomic mutations may have a clear 'loss of fitness' for their insect hosts in vitro. It can also be concluded that such mutations lead to virus variants that are no longer part of the natural transmission cycle between mammalian and insect hosts. Interestingly, analysis of a series of SBV sequences confirmed the S111N mutation exclusively in samples of malformed fetuses and not in blood from viremic animals. The characterization of these changes will allow the definition of protein functions that are critical for only one group of hosts.

Replication of Akabane virus and related orthobunyaviruses in a fetal-bovine-brain-derived cell line.

Akabane virus (AKAV), Aino virus, Peaton virus, Sathuperi virus, and Shamonda virus are arthropod-borne viruses belonging to the order Elliovirales, family Peribunyaviridae, genus Orthobunyavirus. These viruses cause or may cause congenital malformations in ruminants, including hydranencephaly, poliomyelitis, and arthrogryposis, although their pathogenicity may vary among field cases. AKAV may cause relatively severe congenital lesions such as hydranencephaly in calves. Furthermore, strains of AKAV genogroups I and II exhibit different disease courses. Genogroup I strains predominantly cause postnatal viral encephalomyelitis, while genogroup II strains are primarily detected in cases of congenital malformation. However, the biological properties of AKAV and other orthobunyaviruses are insufficiently investigated in hosts in the field and in vitro. Here, we used an immortalized bovine brain cell line (FBBC-1) to investigate viral replication efficiency, cytopathogenicity, and host innate immune responses. AKAV genogroup II and Shamonda virus replicated to higher titers in FBBC-1 cells compared with the other viruses, and only AKAV caused cytopathic effects. These results may be associated with the severe congenital lesions in the brain caused by AKAV genogroup II. AKAV genogroup II strains replicated to higher titers in FBBC-1 cells than AKAV genogroup I strains, suggesting that genogroup II strains replicated more efficiently in fetal brain cells, accounting for the detection of the latter strains mainly in fetal infection cases. Therefore, FBBC-1 cells may serve as a valuable tool for investigating the virulence and tropism of the orthobunyaviruses for bovine neonatal brain tissues in vitro.

First case of Oropouche fever detected in the international border region of the Colombian Amazon: clinical characteristics and molecular diagnosis.

OBJECTIVES: We report the first case of Oropouche fever detected in the border region of Colombia. METHODS: Using a multiplex real-time polymerase chain reaction (PCR), genetic sequencing and clinical characteristics during the dengue epidemic in 2019, a total of 175 samples were analysed, from cases notified to the system epidemiological surveillance such as dengue. FINDINGS: The Oropouche virus (OROV) isolate from Leticia belongs to lineage 2 according to both M and S genome segments maximum likelihood (ML) analysis, shares a common ancestor with samples obtained in Esmeraldas, Ecuador and Turbaco, Colombia. The patient: a woman resident in the border neighbourhood of the municipality of Leticia had the following symptoms: fever, headache, retro-orbital pain and myalgias. MAIN CONCLUSION: This cross-border surveillance can be useful to give an alert about the entry or exit of arboviruses circulation in the region, which are often underreported in public health surveillance systems.

Innate immune response against vector-borne bunyavirus infection and viral countermeasures.

Bunyaviruses are a large group of important viral pathogens that cause significant diseases in humans and animals worldwide. Bunyaviruses are enveloped, single-stranded, negative-sense RNA viruses that infect a wide range of hosts. Upon entry into host cells, the components of viruses are recognized by host innate immune system, leading to the activation of downstream signaling cascades to induce interferons (IFNs) and other proinflammatory cytokines. IFNs bind to their receptors and upregulate the expression of hundreds of interferon-stimulated genes (ISGs). Many ISGs have antiviral activities and confer an antiviral state to host cells. For efficient replication and spread, viruses have evolved different strategies to antagonize IFN-mediated restriction. Here, we discuss recent advances in our understanding of the interactions between bunyaviruses and host innate immune response.

Evaluation of the vector competence for Batai virus of native Culex and exotic Aedes species in Central Europe.

BACKGROUND: Batai virus (BATV) is a zoonotic arbovirus of veterinary importance. A high seroprevalence in cows, sheep and goats and infection in different mosquito species has been observed in Central Europe. Therefore, we studied indigenous as well as exotic species of the genera Culex and Aedes for BATV vector competence at different fluctuating temperature profiles. METHODS: Field caught Culex pipiens biotype pipiens, Culex torrentium, Aedes albopictus and Aedes japonicus japonicus from Germany and Aedes aegypti laboratory colony were infected with BATV strain 53.3 using artificial blood meals. Engorged mosquitoes were kept under four (Culex species) or three (Aedes species) fluctuating temperature profiles (18 ± 5 °C, 21 ± 5 °C, 24 ± 5 °C, 27 ± 5 °C) at a humidity of 70% and a dark/light rhythm of 12:12 for 14 days. Transmission was measured by testing the saliva obtained by forced salivation assay for viable BATV particles. Infection rates were analysed by testing whole mosquitoes for BATV RNA by quantitative reverse transcription PCR. RESULTS: No transmission was detected for Ae. aegypti, Ae. albopictus or Ae. japonicus japonicus. Infection was observed for Cx. p. pipiens, but only in the three conditions with the highest temperatures (21 ± 5 °C, 24 ± 5 °C, 27 ± 5 °C). In Cx. torrentium infection was measured at all tested temperatures with higher infection rates compared with Cx. p. pipiens. Transmission was only detected for Cx. torrentium exclusively at the highest temperature of 27 ± 5 °C. CONCLUSIONS: Within the tested mosquito species, only Cx. torrentium seems to be able to transmit BATV if the climatic conditions are feasible.

Pathogenesis and virulence of Heartland virus.

Heartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease. Moreover, little is known about HRTV-host interactions, viral replication mechanisms, pathogenesis and virulence, further hampering the development of vaccines and antiviral interventions. Here, we aimed to provide a brief review of HRTV epidemiology, molecular biology, pathogenesis and virulence on the basis of published article data to better understand this virus and provide clues for further study.

Evaluating the mosquito vector range for two orthobunyaviruses: Oya virus and Ebinur Lake virus.

BACKGROUND: Mosquito-borne viruses cause various infectious diseases in humans and animals. Oya virus (OYAV) and Ebinur Lake virus (EBIV), belonging to the genus Orthobunyavirus within the family Peribunyaviridae, are recognized as neglected viruses with the potential to pose threats to animal or public health. The evaluation of vector competence is essential for predicting the arbovirus transmission risk. METHODS: To investigate the range of mosquito vectors for OYAV (strain SZC50) and EBIV (strain Cu20-XJ), the susceptibility of four mosquito species (Culex pipiens pallens, Cx. quinquefasciatus, Aedes albopictus, and Ae. aegypti) was measured through artificial oral infection. Then, mosquito species with a high infection rate (IR) were chosen to further evaluate the dissemination rate (DR), transmission rate (TR), and transmission efficiency. The viral RNA in each mosquito sample was determined by RT-qPCR. RESULTS: The results revealed that for OYAV, Cx. pipiens pallens had the highest IR (up to 40.0%) among the four species, but the DR and TR were 4.8% and 0.0%, respectively. For EBIV, Cx. pipiens pallens and Cx. quinquefasciatus had higher IR compared to Ae. albopictus (1.7%). However, the EBIV RNA and infectious virus were detected in Cx. pipiens pallens, with a TR of up to 15.4% and a transmission efficiency of 3.3%. CONCLUSIONS: The findings indicate that Cx. pipiens pallens was susceptible to OYAV but had an extremely low risk of transmitting the virus. Culex pipiens pallens and Cx. quinquefasciatus were susceptible to EBIV, and Cx. pipiens pallens had a higher transmission risk to EBIV than Cx. quinquefasciatus.

Isolation and whole-genome sequence analysis of Balagodu virus in Japan.

Whole-genome sequencing of a virus isolated from Culicoides biting midges in southern Japan in 2020 revealed that it is a strain of Balagodu virus (BLGV; genus Orthobunyavirus; family Peribunyaviridae; order Bunyavirales). A solitary instance of BLGV isolation occurred in India in 1963. All assembled segments comprise complete protein-coding sequences that are similar to those of other orthobunyaviruses. The consensus 3'- and 5'-terminal sequences of orthobunyaviruses' genomic RNAs are also conserved in the Japanese BLGV strain. Here, we update the geographic distribution of BLGV and provide its complete sequence, contributing to the clarification of orthobunyavirus phylogeny.

Nairovirus polymerase mutations associated with the establishment of persistent infection in human cells.

Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne virus of the Orthonairovirus genus, persistently infects tick cells. It has been reported to establish persistent infection in non-human primates, but virological analysis has not yet been performed in human cells. Here, we investigated whether and how nairoviruses persistently infect human cells using Hazara orthonairovirus (HAZV), a surrogate model for CCHFV. We established a human cell line that was persistently infected with HAZV. Surprisingly, virions of persistently infected HAZV (HAZVpi) were not observed in the culture supernatants. There were five mutations (mut1, mut2, mut3, mut4, and mut5) in L protein of HAZVpi. Mutations in L protein of HAZVpi contribute to non-detection of virion in the supernatants. Lmut4 was found to cause low viral growth rate, despite its high polymerase activity. The low growth rate was restored by Lmut2, Lmut3, and Lmut5. The polymerase activity of Lmut1 was extremely low, and recombinant HAZV carrying Lmut1 (rHAZV/Lmut1) was not released into the supernatants. However, genomes of rHAZV/Lmut1 were retained in the infected cells. All mutations (Lmut1-5) found in L protein of HAZVpi were required for experimental reproduction of HAZVpi, and only Lmut1 and Lmut4 were insufficient. We demonstrated that point mutations in viral polymerase contribute to the establishment of persistent HAZV infection. Furthermore, innate immunity was found to be suppressed in HAZVpi-infected cells, which also potentially contributes to viral persistence. This is the first presentation of a possible mechanism behind how nairoviruses establish persistent infection in human cells. IMPORTANCE: We investigated whether and how nairoviruses persistently infect human cells, using Hazara orthonairovirus (HAZV), a surrogate model for Crimean-Congo hemorrhagic fever virus. We established a human cell line that was persistently infected with HAZV. Five mutations were found in L protein of persistently infected HAZV (HAZVpi): mut1, mut2, mut3, mut4, and mut5. Among them, Lmut1 and Lmut4 restricted viral growth by low polymerase activity and low growth rate, respectively, leading to inhibition of viral overgrowth. The restriction of viral growth caused by Lmut1 and Lmut4 was compensated by other mutations, including Lmut2, Lmut3, and Lmut5. Each of the mutations found in L protein of HAZVpi was concluded to cooperatively modulate viral growth, which facilitates the establishment of persistent infection. Suppression of innate immunity also potentially contributes to virus persistence. This is the first presentation of a possible mechanism behind how nairoviruses establish persistent infection in human cells.

Emergence of Oropouche fever in Latin America: a narrative review.

Since its discovery in 1955, the incidence and geographical spread of reported Oropouche virus (OROV) infections have increased. Oropouche fever has been suggested to be one of the most important vector-borne diseases in Latin America. However, both literature on OROV and genomic sequence availability are scarce, with few contributing laboratories worldwide. Three reassortant OROV glycoprotein gene variants termed Iquitos, Madre de Dios, and Perdões virus have been described from humans and non-human primates. OROV predominantly causes acute febrile illness, but severe neurological disease such as meningoencephalitis can occur. Due to unspecific symptoms, laboratory diagnostics are crucial. Several laboratory tests have been developed but robust commercial tests are hardly available. Although OROV is mainly transmitted by biting midges, it has also been detected in several mosquito species and a wide range of vertebrate hosts, which likely facilitates its widespread emergence. However, potential non-human vertebrate reservoirs have not been systematically studied. Robust animal models to investigate pathogenesis and immune responses are not available. Epidemiology, pathogenesis, transmission cycle, cross-protection from infections with OROV reassortants, and the natural history of infection remain unclear. This Review identifies Oropouche fever as a neglected disease and offers recommendations to address existing knowledge gaps, enable risk assessments, and ensure effective public health responses.

A Scoping Review on the Epidemiology of Orthobunyaviruses in Canada, in the Context of Human, Wildlife, and Domestic Animal Host Species.

Background: Mosquito-borne orthobunyaviruses in Canada are a growing public health concern. Orthobunyaviral diseases are commonly underdiagnosed and in Canada, likely underreported as surveillance is passive. No vaccines or specific treatments exist for these disease agents. Further, climate change is facilitating habitat expansion for relevant reservoirs and vectors, and it is likely that the majority of the Canadian population is susceptible to these viruses. Methods: A scoping review was conducted to describe the current state of knowledge on orthobunyavirus epidemiology in Canada. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guideline was used. Literature searches were conducted in six databases and in gray literature. The epidemiology of orthobunyaviruses was characterized for studies focusing on host species, including spatiotemporal patterns, risk factors, and climate change impact. Results: A total of 172 relevant studies were identified from 1734 citations from which 95 addressed host species, including humans, wildlife, and domestic animals including livestock. The orthobunyaviruses-Cache Valley virus (CVV), Jamestown Canyon virus (JCV), Snowshoe Hare virus (SHV), and La Crosse virus (LACV)-were identified, and prevalence was widespread across vertebrate species. CVV, JCV, and SHV were detected across Canada and the United States. LACV was reported only in the United States, predominantly the Mid-Atlantic and Appalachian regions. Disease varied by orthobunyavirus and was associated with age, environment, preexisting compromised immune systems, or livestock breeding schedule. Conclusion: Knowledge gaps included seroprevalence data in Canada, risk factor analyses, particularly for livestock, and disease projections in the context of climate change. Additional surveillance and mitigation strategies, especially accounting for climate change, are needed to guide future public health efforts to prevent orthobunyavirus exposure and disease.

Downregulation of transcription 1 hinders the replication of Dabie bandavirus by promoting the expression of TLR7, TLR8, and TLR9 signaling pathway.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a bunyavirus that causes SFTS, with a case fatality rate of up to 30 %. The innate immune system plays a crucial role in the defense against SFTSV; however, the impact of viral propagation of STFSV on the innate immune system remains unclear. Although proteomics analysis revealed that the expression of the downregulator of transcription 1 (DR1) increased after SFTSV infection, the specific change trend and the functional role of DR1 during viral infection remain unelucidated. In this study, we demonstrate that DR1 was highly expressed in response to SFTSV infection in HEK 293T cells using qRT-PCR and Western blot analysis. Furthermore, viral replication significantly increased the expression of various TLRs, especially TLR9. Our data indicated that DR1 positively regulated the expression of TLRs in HEK 293T cells, DR1 overexpression highly increased the expression of numerous TLRs, whereas RNAi-mediated DR1 silencing decreased TLR expression. Additionally, the myeloid differentiation primary response gene 88 (MyD88)-dependent or TIR-domain-containing adaptor inducing interferon-ß (TRIF)-dependent signaling pathways were highly up- and downregulated by the overexpression and silencing of DR1, respectively. Finally, we report that DR1 stimulates the expression of TLR7, TLR8, and TLR9, thereby upregulating the TRIF-dependent and MyD88-dependent signaling pathways during the SFTSV infection, attenuating viral replication, and enhancing the production of type I interferon and various inflammatory factors, including IL-1ß, IL-6, and IL-8. These results imply that DR1 defends against SFTSV replication by inducing the expression of TLR7, TLR8, and TLR9. Collectively, our findings revealed a novel role and mechanism of DR1 in mediating antiviral responses and innate immunity.

Calcium Influx Regulates the Replication of Several Negative-Strand RNA Viruses Including Severe Fever with Thrombocytopenia Syndrome Virus.

Negative-strand RNA viruses (NSVs) represent one of the most threatening groups of emerging viruses globally. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic emerging virus that was initially reported in 2011 from China. Currently, no licensed vaccines or therapeutic agents have been approved for use against SFTSV. Here, L-type calcium channel blockers obtained from a U.S. Food and Drug Administration (FDA)-approved compound library were identified as effective anti-SFTSV compounds. Manidipine, a representative L-type calcium channel blocker, restricted SFTSV genome replication and exhibited inhibitory effects against other NSVs. The result from the immunofluorescent assay suggested that manidipine inhibited SFTSV N-induced inclusion body formation, which is believed to be important for the virus genome replication. We have shown that calcium possesses at least two different roles in regulating SFTSV genome replication. Inhibition of calcineurin, the activation of which is triggered by calcium influx, using FK506 or cyclosporine was shown to reduce SFTSV production, suggesting the important role of calcium signaling on SFTSV genome replication. In addition, we showed that globular actin, the conversion of which is facilitated by calcium from filamentous actin (actin depolymerization), supports SFTSV genome replication. We also observed an increased survival rate and a reduction of viral load in the spleen in a lethal mouse model of SFTSV infections after manidipine treatment. Overall, these results provide information regarding the importance of calcium for NSV replication and may thereby contribute to the development of broad-scale protective therapies against pathogenic NSVs. IMPORTANCE SFTS is an emerging infectious disease and has a high mortality rate of up to 30%. There are no licensed vaccines or antivirals against SFTS. In this article, L-type calcium channel blockers were identified as anti-SFTSV compounds through an FDA-approved compound library screen. Our results showed the involvement of L-type calcium channel as a common host factor for several different families of NSVs. The formation of an inclusion body, which is induced by SFTSV N, was inhibited by manidipine. Further experiments showed that SFTSV replication required the activation of calcineurin, a downstream effecter of the calcium channel. In addition, we identified that globular actin, the conversion of which is facilitated by calcium from filamentous actin, supports SFTSV genome replication. We also observed an increased survival rate in a lethal mouse model of SFTSV infection after manidipine treatment. These results facilitate both our understanding of the NSV replication mechanism and the development of novel anti-NSV treatment.

Seroprevalence and Risk Factors Associated with Akabane Virus Infection in Sheep and Goats in Fars Province, Iran.

Akabane disease is an arthropod-borne viral disease that affects ruminants. This teratogenic pathogen causes severe economic losses in ruminants worldwide and in Iran; however, it has not received enough attention in Fars province, Iran. Therefore, this study aimed to determine the influence of age, gender, climate, farming system, and history of abortions on the seroprevalence of the Akabane disease in sheep and goats in Fars province. In the present study, Fars province was divided into three climates, and three cities were randomly selected from each climatic region. In each city, two epidemiologic units were selected, and all sheep and goats in each unit were sampled. Overall, 540 serum samples (391 sheep and 149 goats) were collected and examined with the commercial ELISA kit. The results showed that 83 out of 540 (15.4%) samples were seropositive and had antibodies against the Akabane virus (AKAV). The effect of gender and age on the rate of the AKAV was not significant. Animals in warm climates were 4.218 times more likely to have antibodies against the AKAV than animals in cold climates. Females were 1.32 times more likely to exhibit seropositivity. The odds of AKAV infection were higher in animals with an abortion history than in healthy animals. The findings of the present study indicated that the prevalence of the AKAV was high in small ruminants in Fars province. Therefore, it is necessary to conduct more studies to control the risk factors involved in the spread of this virus.

Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1.

Oropouche orthobunyavirus (OROV; Peribunyaviridae) is a mosquito-transmitted virus that causes widespread human febrile illness in South America, with occasional progression to neurologic effects. Host factors mediating the cellular entry of OROV are undefined. Here, we show that OROV uses the host protein low-density lipoprotein-related protein 1 (Lrp1) for efficient cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. In addition, chimeric vesicular stomatitis virus (VSV) expressing OROV glycoproteins (VSV-OROV) bound to the Lrp1 ectodomain in vitro. Furthermore, we demonstrate the biological relevance of the OROV-Lrp1 interaction in a proof-of-concept mouse study in which treatment of mice with RAP at the time of infection reduced tissue viral load and promoted survival from an otherwise lethal infection. These results with OROV, along with the recent finding of Lrp1 as an entry factor for Rift Valley fever virus, highlight the broader significance of Lrp1 in cellular infection by diverse bunyaviruses. Shared strategies for entry, such as the critical function of Lrp1 defined here, provide a foundation for the development of pan-bunyaviral therapeutics.